BPH is a progressive, nearly universal condition in aging men characterized by a nodular enlargement of prostatic tissue resulting, through obstruction of the urethra, in variable degrees of bladder outlet obstruction. The disorder is not a major cause of death, but it is a leading cause of morbidity in elderly men and is associated with a variety of lower urinary tract symptoms. LUTS in males include, inter alia, increased frequency of urination, nocturia, a poor urine stream and hesitancy or delay in starting the urine flow. Chronic consequences of BPH can include hypertrophy of bladder smooth muscle, a decompensated bladder and an increased incidence of urinary tract infection. The specific biochemical, histological and pharmacological properties of the prostate adenoma leading to the bladder outlet obstruction are not yet known. However, the development of BPH is considered to be an inescapable phenomenon for the aging male population. BPH is commonly seen in men over the age of 50 and is observed in approximately 70% of males over the age of 70. Currently, in the United States, the method of choice for treating BPH is the administration of alpha1-adrenoceptor antagonists and, to a lesser extent, surgery, usually involving transurethral resection of the prostate (TURP). The limitations of surgery for treating BPH include the morbidity associated with an operative procedure in elderly men, persistence or recurrence of obstructive and irritative symptoms, as well as the significant cost of surgery. In general, alpha1-adrenoceptor antagonists are used only in the treatment of patients with mild or moderate LUTS.
LUTS are recognized as arising from changes in urethral resistance induced by the enlarging prostate; the outflow of urine is restricted and secondary changes are induced in the bladder. A characteristic pattern of unstable bladder contractions, also known as irritable bladder, is often observed in men with morphological BPH.
Although LUTS can arise from many causes, abnormally high activity in the sympathetic nervous system is considered a prime determinant. Noradrenaline, a neurotransmitter released from sympathetic nerve terminals, contracts the prostatic smooth muscle that surrounds the urethra, increases urethral resistance and thereby reduces uroflow.
Alpha-adrenergic receptors (herein also referred to as “alpha-adrenoceptors” or as “alpha-receptors”) are specific protein recognition sites loaded in the peripheral and central nervous systems and other tissues throughout the body. Neurotransmitters, such as noradrenaline, control many physiological processes via an action on these receptors and thereby transmit information between cells or influence cells or influence biochemical processes within the cell. Many agents capable of modifying noradrenaline activity on alpha-adrenoceptors have been developed over the last 40 years. Drugs active at alpha-adrenoceptors can be broken down into two major classes, agonists and antagonists. Agonists, of which phenylephrine and methoxamine are examples, activate the receptor system in the same way as the endogenous neurotransmitters, adrenaline and noradrenaline. Antagonists, of which phenoxybenzamine and prazosin are examples, do not activate the receptor, but block the actions of the endogenous neurotransmitters.
Different alpha-adrenoceptor types have been discovered over the years including alpha1-adrenoceptors and alpha2-adrenoceptors. These receptor types are now considered to be subdivided further into subtypes including alpha 1A, 1B, 1D, 1H, 1L and 1N.
Alpha1-adrenoceptors are known to mediate the contraction of vascular (arterial and venous) and prostatic smooth muscle. Alpha1-adrenoceptor antagonists have been widely used as first line therapy for the treatment of hypertension and, more recently, for the symptomatic relief of BPH (see Kenny et al, Expert Opin in Invest Drugs, 1995, 4, 915–923).
Alpha-adrenoceptor antagonists are known to relieve the obstruction by causing relaxation of the prostate smooth muscle, a decrease in urethral resistance and increased uroflow. As a result of these changes, male patients with the clinical symptoms of mild-moderate BPH experience a moderate improvement in symptoms. The magnitude of the effect is considerably less than that achieved after surgery.
LUTS, although traditionally associated with BPH, can be found in both men and women. It is noted that women, although they of course do not develop morphological BPH, also suffer due to unstable bladder contractions. The clinical symptoms, particularly frequency and urgency, are similar in women and men.
Bladder excitability is under control of the parasympathetic nervous system that releases the neurotransmitter acetylcholine. Acetylcholine acts on protein recognition sites in the bladder called antimuscarinic receptors, producing an increase in electrical excitability of the bladder and concentration of bladder muscle. Unstable bladder is known to arise due to abnormal excitability or contractility.
Drugs active at muscarinic receptors can be broken into two major classes, agonists and antagonists. Agonists activate the receptor system in the same way as the endogenous neurotransmitter acetylcholine. Muscarinic antagonists (herein referred to as “antimuscarinics”, of which atropine and hyoscine are examples) do not activate the receptor, but block the actions of the endogenous transmitter. Different muscarinic receptor types have been discovered over the years including M1, M2 and M3.
Antimuscarinic-agents are known to relieve many of the symptoms arising from unstable or irritable bladder in women experiencing urinary urge incontinence. The combination of Hyoscyamine and Doxazosin has also been found to be efficacious in treating these symptoms in women (see, e.g., Serels, S., et al., Neurourology and Urodynamics, 17, 31–36 (1998)). However, in normal circumstances, the LUTS arising from BPH-induced unstable bladder contractions in men, should not be treated with antimuscarinics. Indeed the use of antimuscarinics in the treatment of LUTS in men with BPH is contraindicated as urinary retention, requiring catheterization or surgery, may result (see, M. Caine, et al., Br. J. Urol., 47(2), 193–202 (1975))